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Molecular Mechanisms and Targeted Therapies of Breast Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 August 2025 | Viewed by 23132

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Prof. Dr. Piotr Dzięgiel

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Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-367 Wroclaw, Poland
Interests: cancer biology; cell proliferation; cancer biomarkers; tumor microenvironment; immunohistochemistry; histology
Special Issues, Collections and Topics in MDPI journals

Dr. Karolina Jabłońska

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Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
Interests: lung cancer

Dr. Katarzyna Nowińska

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Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
Interests: cancer-associated fibroblasts; tumor microenvironment; cell proliferation; cancer immunotherapy; histology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer is the most common malignancy in women and is a serious public health challenge. Current research focuses on searching for new markers that will allow us to understand the molecular mechanisms of individual breast cancer cell subtypes. The molecular profile of breast cancer cells allows for the development of personalized therapy. Although targeted therapies are more effective and specific than classic therapeutic pathways, they are also associated with the development of molecular resistance. The combination of classic clinical and histopathological tests with omics allows the development of new therapeutic strategies combining classic chemotherapy and immunotherapy with other innovative forms of treatment.

This special issue is open to submission of research articles on molecular aspects of the biology of breast cancer, including diagnostic, prognostic, and predictive biomarkers. The aim of this special issue is to collect the latest knowledge on the signaling pathways involved in the proliferation, and metastasis of breast cancer cells, intercellular communication, and the role of the tumor microenvironment. In addition, we expect work in the areas of genomics, transcriptomics, and epigenetics in the aspect of molecularly targeted therapies. We invite original research and review papers describing the latest achievements and perspectives in this field.

Prof. Dr. Piotr Dzięgiel
Dr. Karolina Jabłońska
Dr. Katarzyna Nowińska
Guest Editors

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Keywords

breast cancer
cancer progression
cancer metastasis
tumor microenvironment
molecular mechanisms
molecular markers
epigenetics
genomics
transcriptomics
EMT
targeted therapies
signaling pathways
exosomes
EMT
hormonal regulation
drugs
apoptosis

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Published Papers (8 papers)

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Research

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32 pages, 6010 KiB

Open AccessArticle

Association of Selected STAT Inhibitors with Prolactin-Induced Protein (PIP) in Breast Cancer

by Karolina Jabłońska, Alicja Kmiecik, Katarzyna Nowińska, Aleksandra Piotrowska, Jarosław Suchański, Katarzyna Ratajczak-Wielgomas, Aleksandra Partyńska, Hanna Romanowicz, Beata Smolarz, Rafał Matkowski and Piotr Dzięgiel

Int. J. Mol. Sci. 2025, 26(4), 1416; https://doi.org/10.3390/ijms26041416 - 7 Feb 2025

Viewed by 864

Abstract

Breast cancer (BC) is the most common cancer in women, and a higher level of prolactin-induced protein (PIP) is associated with better responses to adjuvant chemotherapy. The signal transducer and activator of transcription 5 (STAT5) is a potential regulator of the PIP gene. Prolactin (PRL) and its receptor (PRLR) activate JAK2/STAT5 signaling in BC, which is modulated by inhibitors like suppressors of cytokine signaling (SOCS) proteins and protein inhibitors of activated STAT (PIAS). Using real-time PCR and immunohistochemistry, we studied the relationship between PIP and STAT5 inhibitors in BC. Our findings indicated that PIP and STAT5 levels decrease with a higher tumor grade, size, and tumor/nodes/metastasis (TNM) clinical stage, while nuclear PIAS3 levels increase with tumor progression. Both STAT inhibitors are linked to estrogen and progesterone receptor status. Notably, STAT5 correlates positively with PIP, SOCS3, and PIAS3, suggesting that it may be a favorable prognostic factor. Among the STAT inhibitors, only nuclear PIAS3 expression correlates with PIP. In vitro studies indicated that silencing PIAS3 in T47D cells does not affect PIP expression or sensitivity to doxorubicin (DOX), but T47D control cells with a higher PIP expression are more sensitive to DOX, highlighting the need for further investigation into these mechanisms. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

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20 pages, 2015 KiB

Open AccessArticle

Comprehensive Clinical Genetics, Molecular and Pathological Evaluation Efficiently Assist Diagnostics and Therapy Selection in Breast Cancer Patients with Hereditary Genetic Background

by Petra Nagy, János Papp, Vince Kornél Grolmusz, Anikó Bozsik, Tímea Pócza, Edit Oláh, Attila Patócs and Henriett Butz

Int. J. Mol. Sci. 2024, 25(23), 12546; https://doi.org/10.3390/ijms252312546 - 22 Nov 2024

Viewed by 1158

Abstract

Using multigene panel testing for the diagnostic evaluation of patients with hereditary breast and ovarian cancer (HBOC) syndrome often identifies clinically actionable variants in genes with varying levels of penetrance. High-penetrance genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, TP53) inform specific clinical surveillance and therapeutic decisions, while recommendations for moderate-penetrance genes (ATM, BARD1, BRIP1, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM, NF1, RAD51C, RAD51D) are more limited. A detailed disease history, including pedigree data, helps formulate the most appropriate and personalised management strategies. In this study, we evaluated the clinical benefits of comprehensive hereditary cancer gene panel testing and a pre-sent questionnaire in Hungarian patients with suspected HBOC syndrome. We prospectively enrolled 513 patients referred for HBOC testing. Of these, 463 met the genetic testing criteria, while 50 did not but were tested due to potential therapeutic indications. Additionally, a retrospective cohort of 47 patients who met the testing criteria but had previously only been tested for BRCA1/2 was also analysed. Among the 463 patients in the prospective cohort, 96 (20.7%) harboured pathogenic/likely pathogenic (P/LP) variants—67 in high-penetrance genes and 29 in moderate-penetrance genes. This ratio was similar in the retrospective cohort (6/47; 12.7%). In patients who did not meet the testing criteria, no mutations in high-penetrance genes were found, and only 3 of 50 (6%) harboured P/LP variants in moderate-penetrance genes. Secondary findings (P/LP variants in non-HBOC-associated genes) were identified in two patients. In the prospective cohort, P/LP variants in BRCA1 and BRCA2 were the most prevalent (56/96; 58.3%), and the extended testing doubled the P/LP detection ratio. Among moderate-penetrance genes, five cases (three in the prospective and two in the retrospective cohorts) had P/LP variants in Lynch syndrome-associated genes. Further immunohistochemistry analysis of breast tumour tissues helped clarify the causative role of these variants. Comprehensive clinical and molecular genetic evaluation is beneficial for the diagnosis and management of patients with P/LP variants in hereditary tumour-predisposing genes and can serve as a basis for effective therapy selection, such as PARP inhibitors or immunotherapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

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12 pages, 1345 KiB

Open AccessArticle

The Effect of Statins on Markers of Breast Cancer Proliferation and Apoptosis in Women with In Situ or Early-Stage Invasive Breast Cancer

by Anam Kamal, Julie Boerner, Hadeel Assad, Wei Chen and Michael S. Simon

Int. J. Mol. Sci. 2024, 25(17), 9587; https://doi.org/10.3390/ijms25179587 - 4 Sep 2024

Cited by 2 | Viewed by 1575

Abstract

Statins, inhibitors of HMG-CoA reductase, have been shown to have potential anti-carcinogenic effects through the inhibition of the mevalonate pathway and their impact on Ras and RhoGTAases. Prior studies have demonstrated a reduction in breast tumor proliferation, as well as increased apoptosis, among women with early-stage breast cancer who received statins between the time of diagnosis and the time of surgery. The aim of this study was to evaluate the impact of short-term oral high-potency statin therapy on the expression of markers of breast tumor proliferation, apoptosis, and cell cycle arrest in a window-of-opportunity trial. This single-arm study enrolled 24 women with stage 0-II invasive breast cancer who were administered daily simvastatin (20 mg) for 2–4 weeks between diagnosis and surgical resection. Pre- and post-treatment tumor samples were analyzed for fold changes in Ki-67, cyclin D1, p27, and cleaved caspase-3 (CC3) expression. Out of 24 enrolled participants, 18 received statin treatment and 17 were evaluable for changes in marker expression. There was no significant change in Ki-67 expression (fold change = 1.4, p = 0.597). There were, however, significant increases in the expression of cyclin D1 (fold change = 2.8, p = 0.0003), p27 cytoplasmic (fold change = 3.2, p = 0.025), and CC3 (fold change = 2.1, p = 0.016). Statin treatment was well tolerated, with two reported grade-1 adverse events. These results align with previous window-of-opportunity studies suggesting a pro-apoptotic role of statins in breast cancer. The increased expression of markers of cell cycle arrest and apoptosis seen in this window-of-opportunity study supports further investigation into the anti-cancer properties of statins in larger-scale clinical trials. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

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17 pages, 3587 KiB

Open AccessArticle

Migratory Tumor Cells Cooperate with Cancer Associated Fibroblasts in Hormone Receptor-Positive and HER2-Negative Breast Cancer

by Eun Hye Joo, Sangmin Kim, Donghyun Park, Taeseob Lee, Woong-Yang Park, Kyung Yeon Han and Jeong Eon Lee

Int. J. Mol. Sci. 2024, 25(11), 5876; https://doi.org/10.3390/ijms25115876 - 28 May 2024

Cited by 3 | Viewed by 2077

Abstract

Hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-BC) is the most common type with a favorable prognosis under endocrine therapy. However, it still demonstrates unpredictable progression and recurrences influenced by high tumoral diversity and microenvironmental status. To address these heterogeneous molecular characteristics of HR+/HER2-BC, we aimed to simultaneously characterize its transcriptomic landscape and genetic architecture at the same resolution. Using advanced single-cell RNA and DNA sequencing techniques together, we defined four distinct tumor subtypes. Notably, the migratory tumor subtype was closely linked to genomic alterations of EGFR, related to the tumor-promoting behavior of IL6-positive inflammatory tumor-associated fibroblast, and contributing to poor prognosis. Our study comprehensively utilizes integrated analysis to uncover the complex dynamics of this breast cancer subtype, highlighting the pivotal role of the migratory tumor subtype in influencing surrounding cells. This sheds light on potential therapeutic targets by offering enhanced insights for HR+/HER2-BC treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

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18 pages, 4780 KiB

Open AccessArticle

Harnessing Metformin’s Immunomodulatory Effects on Immune Cells to Combat Breast Cancer

by Andjela Petrovic, Ivan Jovanovic, Bojan Stojanovic, Milica Dimitrijevic Stojanovic, Bojana S. Stojanovic, Milena Jurisevic, Bojana Simovic Markovic, Marina Jovanovic, Milan Jovanovic, Mihailo Jovanovic and Nevena Gajovic

Int. J. Mol. Sci. 2024, 25(11), 5869; https://doi.org/10.3390/ijms25115869 - 28 May 2024

Cited by 5 | Viewed by 2358

Abstract

Metformin, a medication known for its anti-glycemic properties, also demonstrates potent immune system activation. In our study, using a 4T1 breast cancer model in BALB/C WT mice, we examined metformin’s impact on the functional phenotype of multiple immune cells, with a specific emphasis on natural killer T (NKT) cells due to their understudied role in this context. Metformin administration delayed the appearance and growth of carcinoma. Furthermore, metformin increased the percentage of IFN-γ⁺ NKT cells, and enhanced CD107a expression, as measured by MFI, while decreasing PD-1⁺, FoxP3⁺, and IL-10⁺ NKT cells in spleens of metformin-treated mice. In primary tumors, metformin increased the percentage of NKp46⁺ NKT cells and increased FasL expression, while lowering the percentages of FoxP3⁺, PD-1⁺, and IL-10-producing NKT cells and KLRG1 expression. Activation markers increased, and immunosuppressive markers declined in T cells from both the spleen and tumors. Furthermore, metformin decreased IL-10⁺ and FoxP3⁺ Tregs, along with Gr-1⁺ myeloid-derived suppressor cells (MDSCs) in spleens, and in tumor tissue, it decreased IL-10⁺ and FoxP3⁺ Tregs, Gr-1⁺, NF-κB⁺, and iNOS⁺ MDSCs, and iNOS⁺ dendritic cells (DCs), while increasing the DCs quantity. Additionally, increased expression levels of MIP1a, STAT4, and NFAT in splenocytes were found. These comprehensive findings illustrate metformin’s broad immunomodulatory impact across a variety of immune cells, including stimulating NKT cells and T cells, while inhibiting Tregs and MDSCs. This dynamic modulation may potentiate its use in cancer immunotherapy, highlighting its potential to modulate the tumor microenvironment across a spectrum of immune cell types. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

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Review

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25 pages, 2143 KiB

Open AccessReview

Cell Death: Mechanisms and Potential Targets in Breast Cancer Therapy

by Jiangying Qian, Linna Zhao, Ling Xu, Jin Zhao, Yongxu Tang, Min Yu, Jie Lin, Lei Ding and Qinghua Cui

Int. J. Mol. Sci. 2024, 25(17), 9703; https://doi.org/10.3390/ijms25179703 - 7 Sep 2024

Cited by 3 | Viewed by 3626

Abstract

Breast cancer (BC) has become the most life-threatening cancer to women worldwide, with multiple subtypes, poor prognosis, and rising mortality. The molecular heterogeneity of BC limits the efficacy and represents challenges for existing therapies, mainly due to the unpredictable clinical response, the reason for which probably lies in the interactions and alterations of diverse cell death pathways. However, most studies and drugs have focused on a single type of cell death, while the therapeutic opportunities related to other cell death pathways are often neglected. Therefore, it is critical to identify the predominant type of cell death, the transition to different cell death patterns during treatment, and the underlying regulatory mechanisms in BC. In this review, we summarize the characteristics of various forms of cell death, including PANoptosis (pyroptosis, apoptosis, necroptosis), autophagy, ferroptosis, and cuproptosis, and discuss their triggers and signaling cascades in BC, which may provide a reference for future pathogenesis research and allow for the development of novel targeted therapeutics in BC. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

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16 pages, 294 KiB

Open AccessReview

Immunotherapy in Breast Cancer

by Kathrin Dvir, Sara Giordano and Jose Pablo Leone

Int. J. Mol. Sci. 2024, 25(14), 7517; https://doi.org/10.3390/ijms25147517 - 9 Jul 2024

Cited by 19 | Viewed by 9412

Abstract

Breast cancer is a disease encompassing a spectrum of molecular subtypes and clinical presentations, each with distinct prognostic implications and treatment responses. Breast cancer has traditionally been considered an immunologically “cold” tumor, unresponsive to immunotherapy. However, clinical trials in recent years have found immunotherapy to be an efficacious therapeutic option for select patients. Breast cancer is categorized into different subtypes ranging from the most common positive hormone receptor (HR+), human epidermal growth factor receptor 2 (HER2)—negative type, to less frequent HER2− positive breast cancer and triple-negative breast cancer (TNBC), highlighting the necessity for tailored treatment strategies aimed at maximizing patient outcomes. Despite notable progress in early detection and new therapeutic modalities, breast cancer remains the second leading cause of cancer death in the USA. Moreover, in recent decades, breast cancer incidence rates have been increasing, especially in women younger than the age of 50. This has prompted the exploration of new therapeutic approaches to address this trend, offering new therapeutic prospects for breast cancer patients. Immunotherapy is a class of therapeutic agents that has revolutionized the treatment landscape of many cancers, namely melanoma, lung cancer, and gastroesophageal cancers, amongst others. Though belatedly, immunotherapy has entered the treatment armamentarium of breast cancer, with the approval of pembrolizumab in combination with chemotherapy in triple-negative breast cancer (TNBC) in the neoadjuvant and advanced settings, thereby paving the path for further research and integration of immune checkpoint inhibitors in other subtypes of breast cancer. Trials exploring various combination therapies to harness the power of immunotherapy in symbiosis with various chemotherapeutic agents are ongoing in hopes of improving response rates and prolonging survival for breast cancer patients. Biomarkers and precise patient selection for the utilization of immunotherapy remain cardinal and are currently under investigation, with some biomarkers showing promise, such as Program Death Lignat-1 (PDL-1) Combined Positive Score, Tumor Mutation Burden (TMB), and Tumor Infiltrating Lymphocytes (TILs). This review will present the current landscape of immunotherapy, particularly checkpoint inhibitors, in different types of breast cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

23 pages, 1784 KiB

Open AccessReview

The Immune Response of Cancer Cells in Breast and Gynecologic Neoplasms

by Katarzyna Rakoczy, Justyna Kaczor, Adam Sołtyk, Natalia Szymańska, Jakub Stecko, Małgorzata Drąg-Zalesińska and Julita Kulbacka

Int. J. Mol. Sci. 2024, 25(11), 6206; https://doi.org/10.3390/ijms25116206 - 5 Jun 2024

Viewed by 1383

Abstract

Cancer diseases constitute a major health problem which leads to the death of millions of people annually. They are unique among other diseases because cancer cells can perfectly adapt to the environment that they create themselves. This environment is usually highly hostile and for normal cells it would be hugely difficult to survive, however neoplastic cells not only can survive but also manage to proliferate. One of the reasons is that they can alter immunological pathways which allow them to be flexible and change their phenotype to the one needed in specific conditions. The aim of this paper is to describe some of these immunological pathways that play significant roles in gynecologic neoplasms as well as review recent research in this field. It is of high importance to possess extensive knowledge about these processes, as greater understanding leads to creating more specialized therapies which may prove highly effective in the future. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)

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